scholarly journals Chronic inflammation within the vascular wall in pulmonary arterial hypertension: more than a spectator

2019 ◽  
Vol 116 (5) ◽  
pp. 885-893 ◽  
Author(s):  
Alice Huertas ◽  
Ly Tu ◽  
Marc Humbert ◽  
Christophe Guignabert
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Wall ◽  
Direct Role ◽  
Future Studies ◽  
Functional Changes ◽  
Persistent Inflammation ◽  
Tunica Adventitia ◽  
Pulmonary Arterial ◽  
Tunica Intima

Abstract This review seeks to provide an update of preclinical findings and available clinical data on the chronic persistent inflammation and its direct role on the pulmonary arterial hypertension (PAH) progression. We reviewed the different mechanisms by which the inflammatory and immune pathways contribute to the structural and functional changes occurring in the three vascular compartments: the tunica intima, tunica media, and tunica adventitia. We also discussed how these inflammatory mediator changes may serve as a biomarker of the PAH progression and summarize unanswered questions and opportunities for future studies in this area.

Model Characterization of Pulmonary Arterial Hypertension: Analysis of Lung Pathology with Respect to Human Disease

2020 ◽  
Author(s):  
◽  
Eptisam lambu
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Human Disease ◽  
Vascular Remodeling ◽  
Vascular Wall ◽  
Lung Pathology ◽  
Pulmonary Arterial ◽  
Lung Pathogenesis ◽  
Arterial Endothelial Cells

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease characterized by abnormal high blood pressure in the pulmonary artery, or increased pulmonary vascular resistance (PVR), caused by obstruction in the small arteries of the lung. Increased PVR is also thought to be caused by abnormal vascular remodeling, due to thickening of the pulmonary vascular wall resulting from significant hypertrophy of pulmonary arterial smooth-muscle cells (PASMCs) and increased proliferation/impaired apoptosis of pulmonary arterial endothelial cells (PAECs). Herein, we investigated the mechanisms and explored molecular pathways mediating the lung pathogenesis in two PAH rat models: Monocrotaline (MCT) and Sugen5416/Hypoxia (SuHx). We analyzed these disease models to determine where the vasculature shows the most severe PAH pathology and which model best recapitulates the human disease. We investigated the role vascular remodeling, hypoxia, cell proliferation, apoptosis, DNA damage and inflammation play in the pathogenesis of PAH. Neither model recapitulated all features of the human disease, however each model presented with some of the pathology seen in PAH patients.

scholarly journals Organ-level right ventricular dysfunction with preserved Frank-Starling mechanism in a mouse model of pulmonary arterial hypertension

2018 ◽  
Vol 124 (5) ◽  
pp. 1244-1253 ◽  
Author(s):  
Zhijie Wang ◽  
Jitandrakumar R. Patel ◽  
David A. Schreier ◽  
Timothy A. Hacker ◽  
Richard L. Moss ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Pressure Overload ◽  
Multiple Time ◽  
Functional Changes ◽  
Pulmonary Arterial ◽  
Organ Level ◽  
Subcellular Level ◽  
Insight Into

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is due to right ventricular (RV) failure. It is unclear whether RV dysfunction initiates at the organ level or the subcellular level or both. We hypothesized that chronic pressure overload-induced RV dysfunction begins at the organ level with preserved Frank-Starling mechanism in myocytes. To test this hypothesis, we induced PAH with Sugen + hypoxia (HySu) in mice and measured RV whole organ and subcellular functional changes by in vivo pressure-volume measurements and in vitro trabeculae length-tension measurements, respectively, at multiple time points for up to 56 days. We observed progressive changes in RV function at the organ level: in contrast to early PAH (14-day HySu), in late PAH (56-day HySu) ejection fraction and ventricular-vascular coupling were decreased. At the subcellular level, direct measurements of myofilament contraction showed that RV contractile force was similarly increased at any stage of PAH development. Moreover, cross-bridge kinetics were not changed and length dependence of force development (Frank-Starling relation) were not different from baseline in any PAH group. Histological examinations confirmed increased cardiomyocyte cross-sectional area and decreased von Willebrand factor expression in RVs with PAH. In summary, RV dysfunction developed at the organ level with preserved Frank-Starling mechanism in myofilaments, and these results provide novel insight into the development of RV dysfunction, which is critical to understanding the mechanisms of RV failure. NEW & NOTEWORTHY A multiscale investigation of pulmonary artery pressure overload in mice showed time-dependent organ-level right ventricular (RV) dysfunction with preserved Frank-Starling relations in myofilaments. Our findings provide novel insight into the development of RV dysfunction, which is critical to understanding mechanisms of RV failure.

scholarly journals Iloprost for acute tests in patients with pulmonary arterial hypertension

2012 ◽  
Vol 9 (4) ◽  
pp. 54-57
Author(s):  
E A Belyatko ◽  
N M Danilov ◽  
Y G Matchin ◽  
T V Martynyuk ◽  
I E Chazova
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Intima Media Thickness ◽  
Vascular Wall ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Hemodynamic Changes ◽  
Pulmonary Arterial ◽  
Inner Diameter

Objective: in our study, iloprost was used as a drug for acute tests in patients with pulmonary arterial hypertension (PAH). Design and Method. We included 7 pts with pulmonary arterial hypertension (PAH): 5 females and 2 males, average age 32,0±12,0 years. All patients underwent right heart catheterization including acute tests with both nitric oxide and Iloprost. In addition to hemodynamic changes the intravascular ultrasound (IVUS) parameters were analyzed. We used parameters such as: intima-media thickness, the pulsatility index (PI), the outer and inner diameter of the vessel, the area of the vascular wall. Results. Compared with the action of nitric oxide, the degree of reduction of medium pulmonary arterial pressure (mPAP) after Iloprost was 17,2±5 and 25,37±9 mm Hg respectively, and pulmonary vascular resistance (PVR) 251,4±120 and 276±129 dynes×c×cm-5 respectively (p

scholarly journals Do single or sequential measurements of leptin and adiponectin in plasma have prognostic value in pulmonary arterial hypertension?

2017 ◽  
Vol 7 (3) ◽  
pp. 727-729 ◽  
Author(s):  
Adriano R. Tonelli ◽  
Wassim H. Fares ◽  
Wael Dakkak ◽  
Youlan Rao ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Functional Class ◽  
Double Blind ◽  
Small Magnitude ◽  
Functional Changes ◽  
Background Therapy ◽  
Pulmonary Arterial ◽  
Plasma Leptin

Leptin (a neuroendocrine peptide that enhances metabolism and acts on the hypothalamus to suppress appetite) and adiponectin (a protein that has insulin-sensitizing, anti-inflammatory, and antiproliferative properties) are involved in the pathobiology of pulmonary arterial hypertension (PAH). We hypothesized that plasma leptin and adiponectin as well as the leptin/adiponectin ratio are abnormal in PAH patients and their levels track with disease severity and functional changes during follow-up. We tested this hypothesis in a cohort of patients included in the 16-week, international, multicenter, double-blind, placebo-controlled FREEDOM-C2 study. Blood was collected at baseline and week 16 in 178 out of 310 randomized patients with PAH. Baseline plasma leptin and adiponectin concentrations were 25 ± 31 ng/mL and 7.8 ± 6.1 ug/mL, respectively. Leptin, adiponectin, and leptin/adiponectin (mean ± SD) changes at 16 week were of small magnitude. Leptin at baseline was significantly associated with older age, higher BMI, higher Borg dyspnea index, and lower NT-pro BNP. Women had higher levels of leptin than men (30.5 ± 33.2 versus 7.2 ± 6.4 ng/mL), even when adjusting for background therapy and etiology (linear regression: β = 21.8, P < 0.001). Adiponectin was negatively associated with BMI and positively associated with NT-pro BNP. Changes in leptin, adiponectin, and leptin/adiponectin ratio adjusted for weight at 16 weeks did not predict functional class, distance walk in 6 min or survival at one, two, three, or four years. Plasma leptin and adiponectin at baseline and their change at 16-week do not appear to significantly impact prognosis in PAH.

scholarly journals Image-based computational assessment of vascular wall mechanics and hemodynamics in pulmonary arterial hypertension patients

2018 ◽  
Vol 68 ◽  
pp. 84-92 ◽  
Author(s):  
Byron A. Zambrano ◽  
Nathan A. McLean ◽  
Xiaodan Zhao ◽  
Ju-Le Tan ◽  
Liang Zhong ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Wall ◽  
Pulmonary Arterial

scholarly journals Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension

2021 ◽  
Vol 22 (17) ◽  
pp. 9105
Author(s):  
Malik Bisserier ◽  
Michael G. Katz ◽  
Carlos Bueno-Beti ◽  
Agnieszka Brojakowska ◽  
Shihong Zhang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Potential ◽  
Combined Therapy ◽  
Pulmonary Arteries ◽  
Combination Therapies ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a devastating lung disease characterized by the progressive obstruction of the distal pulmonary arteries (PA). Structural and functional alteration of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) contributes to PA wall remodeling and vascular resistance, which may lead to maladaptive right ventricular (RV) failure and, ultimately, death. Here, we found that decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in the lung samples of PAH patients was associated with the down-regulation of bone morphogenetic protein receptor type 2 (BMPR2) and the activation of signal transducer and activator of transcription 3 (STAT3). Our results showed that the antiproliferative properties of SERCA2a are mediated through the STAT3/BMPR2 pathway. At the molecular level, transcriptome analysis of PASMCs co-overexpressing SERCA2a and BMPR2 identified STAT3 amongst the most highly regulated transcription factors. Using a specific siRNA and a potent pharmacological STAT3 inhibitor (STAT3i, HJC0152), we found that SERCA2a potentiated BMPR2 expression by repressing STAT3 activity in PASMCs and PAECs. In vivo, we used a validated and efficient model of severe PAH induced by unilateral left pneumonectomy combined with monocrotaline (PNT/MCT) to further evaluate the therapeutic potential of single and combination therapies using adeno-associated virus (AAV) technology and a STAT3i. We found that intratracheal delivery of AAV1 encoding SERCA2 or BMPR2 alone or STAT3i was sufficient to reduce the mean PA pressure and vascular remodeling while improving RV systolic pressures, RV ejection fraction, and cardiac remodeling. Interestingly, we found that combined therapy of AAV1.hSERCA2a with AAV1.hBMPR2 or STAT3i enhanced the beneficial effects of SERCA2a. Finally, we used cardiac magnetic resonance imaging to measure RV function and found that therapies using AAV1.hSERCA2a alone or combined with STAT3i significantly inhibited RV structural and functional changes in PNT/MCT-induced PAH. In conclusion, our study demonstrated that combination therapies using SERCA2a gene transfer with a STAT3 inhibitor could represent a new promising therapeutic alternative to inhibit PAH and to restore BMPR2 expression by limiting STAT3 activity.

scholarly journals Human Immunodeficiency Virus and Pulmonary Arterial Hypertension

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Aibek E. Mirrakhimov ◽  
Alaa M. Ali ◽  
Aram Barbaryan ◽  
Suartcha Prueksaritanond
Keyword(s):  
Human Immunodeficiency Virus ◽  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Clinical Presentation ◽  
Rare Complication ◽  
Viral Proteins ◽  
Future Studies ◽  
Immunodeficiency Virus ◽  
Pulmonary Arterial

Human immunodeficiency virus- (HIV-) related pulmonary arterial hypertension (PAH) is a rare complication of HIV infection. The pathophysiology of HIV-related PAH is complex, with viral proteins seeming to play the major role. However, other factors, such as coinfection with other microorganisms and HIV-related systemic inflammation, might also contribute. The clinical presentation of HIV-related PAH and diagnosis is similar to other forms of pulmonary hypertension. Both PAH-specific therapies and HAART are important in HIV-related PAH management. Future studies investigating the pathogenesis are needed to discover new therapeutic targets and treatments.

The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis—ten years later

2020 ◽  
Vol 318 (6) ◽  
pp. L1115-L1130 ◽  
Author(s):  
Carlyne D. Cool ◽  
Wolfgang M. Kuebler ◽  
Harm Jan Bogaard ◽  
Edda Spiekerkoetter ◽  
Mark R. Nicolls ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Cell Injury ◽  
Vascular Endothelial Cell ◽  
Treatment Strategies ◽  
Vascular Wall ◽  
Vascular Endothelial ◽  
Proliferating Cells ◽  
Bone Marrow Derived Cells ◽  
Pulmonary Arterial

Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the evolution of phenotypically altered, apoptosis-resistant, proliferating cells and an inflammatory vascular immune response. Although there may be a vasoconstrictive disease component, the increased pulmonary vascular shear stress in established PAH is caused largely by the vascular wall pathology. In this review, we revisit the “quasi-malignancy concept” of severe PAH and examine to what extent the hallmarks of PAH can be compared with the hallmarks of cancer. The cancer model of severe PAH, based on the growth of abnormal vascular and bone marrow-derived cells, may enable the emergence of novel cell-based PAH treatment strategies.

Sign in / Sign up

Export Citation Format

Share Document